MicroRNAs regulate T-cell production of interleukin-9 and identify hypoxia-inducible factor-2a as an important regulator of T helper 9 and regularoty T-cell differentiation

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Singh, Y ; Garden, O A ; Lang, F ; Cobb, B S (2016)

MicroRNAs (miRNAs) regulate many aspects of helper T cell (Th) development and function. Here we found that they are required for the suppression of interleukin‐9 (IL‐9) expression in Th9 cells and other Th subsets. Two highly related miRNAs (miR‐15b and miR‐16) that we previously found to play an important role in regulatory T (Treg) cell differentiation were capable of suppressing IL‐9 expression when they were over‐expressed in Th9 cells. We used these miRNAs as tools to identify novel regulators of IL‐9 expression and found that they could regulate the expression of Epas1, which encodes hypoxia‐inducible factor (HIF)‐2α. HIF proteins regulate metabolic pathway usage that is important in determining appropriate Th differentiation. The related protein, HIF‐1α enhances Th17 differentiation and inhibits Treg cell differentiation. Here we found that HIF‐2α was required for IL‐9 expression in Th9 cells, but its expression was not sufficient in other Th subsets. Furthermore, HIF‐2α suppressed Treg cell differentiation like HIF‐1α, demonstrating both similar and distinct roles of the HIF proteins in Th differentiation and adding a further dimension to their function. Ironically, even though miR‐15b and miR‐16 suppressed HIF‐2α expression in Treg cells, inhibiting their function in Treg cells did not lead to an increase in IL‐9 expression. Therefore, the physiologically relevant miRNAs that regulate IL‐9 expression in Treg cells and other subsets remain unknown. Nevertheless, the analysis of miR‐15b and miR‐16 function led to the discovery of the importance of HIF‐2α so this work demonstrated the utility of studying miRNA function to identify novel regulatory pathways in helper T‐cell development.
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